(R-(E)-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3 -(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium salt, also known by the name montelukast sodium, is represented by the structural formula I below:

Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis.
Montelukast sodium, formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.
Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480,717. The synthesis of montelukast sodium, as taught in patent EP 480,717, involves coupling methyl 1-(mercaptomethyl)cyclopropaneacetate with (S)-1-(3-(2-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3(-2-(1-hydroxy-1-methylethyl)-phenyl)propyl methanesulfonate, followed by hydrolysis of the resulting methyl ester so as to form a free acid, which is followed by conversion of the free acid into a corresponding sodium salt.
U.S. Pat. No. 5,614,632 (hereinafter the '632 patent) teaches a method of preparing crystalline montelukast sodium, which involves the preparation of the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid as an intermediate, followed by condensation thereof with 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol, to yield montelukast acid. This process comprises converting 1-(mercaptomethyl)-cyclopropaneacetic acid into a dilithium dianion by reaction with lithium bases such as n-butyl lithium in a solvent mixture at low temperature and reacting the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid with the mesylate intermediate, mentioned earlier, which has limited stability and is therefore prepared in situ. Thus, upon coupling of the mesylate 2-(2-2(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxy propyl) phenyl)-2-propanol with the dilithium dianoin, montelukast acid is obtained as a viscous oil. The resulting montelukast acid is converted, via the corresponding dicyclohexyl ammonium salt, into montelukast sodium.
The '632 patent describes also a process for preparing the side-chain precursor 1-(mercaptomethyl)cyclopropaneacetic acid, which is depicted in Scheme 1 below.

The first step comprises converting the starting material 1,1-cyclopropanedimethanol II into the corresponding cyclic sulfite III by using thionyl chloride and in the presence of a base such as diisopropylethylamine. The cyclic sulfite III is treated with catalytic amount of sodium iodide and sodium cyanide to obtain the compound 1-(hydroxymethyl)cyclopropaneacetonitrile IV, which is converted into the corresponding mesylate 1-(methanesulfonyloxymethyl)-cyclopropaneacetonitrile V, by using methanesulfonyl chloride in the presence of a base. Compound V is treated with potassium thioacetate or thioacetic acid in the presence of a base to yield the compound 1-(acetylthiomethyl)-cyclopropaneacetonitrile VI. In the last step, compound VI is converted into 1-(mercaptomethyl)cyclopropaneacetic acid VII by reacting compound VI in a biphasic solvent system comprising toluene and aqueous NaOH for 16-18 hours.
The intermediate 1-(mercaptomethyl)cyclopropaneacetic acid is not stable and is being prone to oxidation like many other thiols, as generally depicted in Scheme 2 below.

This is evident from example 4 of the '632 patent, which tackles the instability problem of 1-(mercaptomethyl)cyclopropaneacetic acid by carrying out the reaction under nitrogen. In addition, the use of sodium cyanide or thioacetic acid is unfavorable on industrial scale because of high toxicity or pungent odor.
U.S. Pat. No. 6,512,140 (hereinafter the '140 patent) provides a process for preparing the compound 1-(mercaptomethyl)cyclopropaneacetic acid, which is described in Scheme 3 below.

The process comprises reacting 1-(hydroxymethyl)cyclopropaneacetonitrile IV with an acid, to thus obtain the corresponding mixture of cyclic imino ether and halo-amide (VIII and IX respectively), which when reacted with thiourea provides the corresponding amide-isothiuronium salt X. Hydrolysis of the amide-isothiuronium salt X followed by an in situ oxidation affords the intermediate 1-(mercaptomethyl)cyclopropaneacetic acid disulfide XI, which affords the final product upon treatment with a solution containing ammonium hydroxide and metal zinc for 3.5 hours followed by treatment with citric acid. Thus, the oxidation problem of the corresponding amide was solved by dimerizing the thiolamide, which may yield the requested product by reduction. However, the problem with the process provided in the '140 patent is that it is lengthy and contains laborious procedures.
Unstable intermediates such as 1-(mercaptomethyl)cyclopropaneacetic acid (and the need to use special reaction conditions thereof) are not easily amendable to industrial scale production. Hence, there is still a need in the art for a side-chain precursor that is stable on one hand, and which may be more conveniently prepared and used in the synthesis of montelukast sodium on the other hand.